cbd and epilepsy study

Cannabidiol (CBD) is one of the major components of the Cannabis sativa plant. This phytocannabinoid was isolated in the 1940s and thoroughly studied thereafter [4]. Cannabidiol is not only used as a food supplement or for general well-being purposes, in fact, it is under investigation for a board variety of disorders, for example, mood disorders, anxiety, pain, or epilepsy [4, 5]. Cannabidiol can be synthesized (synthetic CBD) as well as extracted from C. sativa (plant derived). For different formulas [with different tetrahydrocannabidiol (THC) co-content], CBD-rich cannabis to purified CBD, to highly purified pharmaceutical-grade CBD (with THC content lower than 0.2%) are available.

Key Points

Over the past few years, the interest in using CBD for general well-being as well as a treatment option for different diseases has risen. This deluge of personal experiences and reports has inspired patients with epilepsy and their families to try CBD for seizure control. A famous report detailed the treatment course of a 5-year-old girl with Dravet syndrome (DS) who experienced up to 50 bilateral tonic-clonic seizures per month. She experienced a > 90% reduction in seizures with CBD-rich cannabis treatment. This attracted immense attention and raised the interest in treating patients with epilepsy with CBD [10]. Because of a massive amount of media reporting and the expectations and wishes of severely affected patients with epilepsy, the demand for medical cannabis and CBD treatment increased dramatically [11]. In the USA, because of the legal restrictions of cannabis and its compounds, some families even moved to other states with easier access to medical cannabis and CBD to receive this treatment for their children with epilepsy [12].

First Cannabidiol Treatment in Epilepsy

Four randomized, controlled, double-blind studies were carried out in childhood-onset epilepsies: two in Lennox–Gastaut syndrome (LGS) and two in patients with DS. All of them used plant-derived, pharmaceutical-grade CBD from the same company.

Cbd and epilepsy study

Two phase 2 clinical trials <"type":"clinical-trial","attrs":<"text":"NCT03355300","term_id":"NCT03355300">> NCT03355300 and <"type":"clinical-trial","attrs":<"text":"NCT03336242","term_id":"NCT03336242">> NCT03336242 are expecting to recruit about 30 pediatric patients (3 to 17 years), with treatment-resistant childhood absence seizure. Both studies will include three experimental treatment cohorts (20, 30 and 40 mg/kg/day). <"type":"clinical-trial","attrs":<"text":"NCT03336242","term_id":"NCT03336242">> NCT03336242 will assess efficacy, safety, tolerability and pharmacokinetics of CBD oral solution after 4 weeks of treatment. This study will include a 4-week screening period and a 5 or 10 day titration period (depending on study cohort), a 4-week treatment period followed by 5-day tapering for doses >20 mg/kg/day and a 4-week follow-up period. Instead, <"type":"clinical-trial","attrs":<"text":"NCT03355300","term_id":"NCT03355300">> NCT03355300 will evaluate the long-term (up to approximately 54 weeks) safety and tolerability of the CBD oral solution, monitoring the incidence of SAEs and AEs during and after treatment. For both trials, the final data collection and the results are expected by the end of the year 2019.

The clinical trials of phase I <"type":"clinical-trial","attrs":<"text":"NCT02695537","term_id":"NCT02695537">> NCT02695537 and <"type":"clinical-trial","attrs":<"text":"NCT02700412","term_id":"NCT02700412">> NCT02700412, will evaluate prospectively and longitudinally the safety and tolerability of CBD oral solution (Epidiolex) at various doses, between 5 mg/kg/day and 25 mg/kg/day with additional titration in some cases up to 50 mg/kg/day. These two trials will enroll both 100 patients with drug-resistant epilepsy. Clinical trial <"type":"clinical-trial","attrs":<"text":"NCT02695537","term_id":"NCT02695537">> NCT02695537 will enroll patients aged 1 to 18 years, while the <"type":"clinical-trial","attrs":<"text":"NCT02700412","term_id":"NCT02700412">> NCT02700412 patients aged 17 to 99 years. However, Gaston, et al. [78] evaluated possible CBD interactions with antiepileptic drugs typically used in 39 adults and 42 children of these trials. An analysis was carried out to check for non-uniform changes in both the CBD dose and the dose of other AEDs. In the two combined arms (pediatric and adult) the results recorded linear increases in serum levels of topiramate, rufinamide and [N-CLB] and linear decreases in CLB levels correlate with increasing CBD does. However, there were no significant changes in the levels of other AEDs analyzed (valproate, levetiracetam, phenobarbital, clonazepam, phenytoin, carbamazepine, lamotrigine, oxcarbazepine, ethosuximide, vigabatrin, ezogabine, pregabalin, perampanel and lacosamide). During the study, six adults and eight children showed sedation. The intake of concomitant CBD and valproate resulted in high levels of AST and ALT. Liver function tests showed elevated damage greater than three times the normal limit in four children who dropped out of the study, while the damages of about twice the upper normal limit in eight adults were resolved with valproate withdrawal. A major onset of somnolence following the concomitant administration of CBD and CLB and high levels of transaminases following co-administration of CBD and valproate was also recorded in another study [73] and in clinical trial <"type":"clinical-trial","attrs":<"text":"NCT02224690","term_id":"NCT02224690">> NCT02224690. In conclusion, the results obtained by the researchers show that the use of CBD with other drugs can be considered safe. On the contrary concomitant use of CBD with valproate is not recommended as a significant liver dysfunction has been observed. Probably because CBD enhances the toxic action of valproate. The interaction between CBD and CLB was also highlighted. Since both of these drugs are metabolized of the cytochrome P450 pathway, this interaction can often induce high plasma levels of n-CLB. Therefore, it is important to monitor this drug-drug interaction. However, as the adverse effects occurring, in this case, are not serious, the concomitant use of CBD with CLB can be considered safe and above all effective, especially in pediatric patients with refractory epilepsy. Part of the results of <"type":"clinical-trial","attrs":<"text":"NCT02695537","term_id":"NCT02695537">> NCT02695537 and <"type":"clinical-trial","attrs":<"text":"NCT02700412","term_id":"NCT02700412">> NCT02700412 were described by Szaflarski, et al. [79]. The study showed the efficacy and safety of Epidiolex in 72 children and 60 adults. The results obtained show an average reduction of all types of seizures of 63.6% with difference significant between baseline and 12 weeks. The reduction in seizures seems to have remained stable, in fact, there were no significant differences between 12 and 24 weeks and between 24 and 48 weeks. The severity of the seizures assessed by the Chalfont Seizure Severity Scale (CSSS) also showed an improvement from a baseline score of 80.7 to enroll at 39.3 at 12 weeks with CSSS scores stable even between 12 and 24 weeks and between 24 and 48 weeks. The analysis of AE Profile indicates a significant improvement in the presence/severity of adverse events between the baseline and 12 weeks with stable AEDs thereafter without significant differences between 12 and 24 weeks and between 24 and 48 weeks. The results of this study show significant improvements in the profile of adverse events, in the severity of crises and in reducing the frequency of seizures as early as 12 weeks; improvements that have been maintained during the 48 weeks of treatment.

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Another study to evaluate the efficacy of the CBD oral solution (GWP42003-P) as a therapy for drug-resistant epilepsy in TSC was conducted by Hess, et al. [82] (approved by Massachusetts General Hospital Institutional Review Board and U.S. Food and Drug Administration). Of the 56 patients enrolled in this study, only 18 patients (aged 2 to 31 years) were evaluated because they were affected by TSC. At the time of enrolment, patients were taking between one and seven anti-epileptic drugs, such as lacosamide (n = 14), CLB (n = 10), levetiracetam (n = 7), lamotrigine (n = 5), valproic acid (n = 3) and rufinamide (n = 3). Treatment started at a dose of 5 mg/kg/day. This dose was increased by 5 mg/kg/day every week up to the initial maximum dose of 50 mg/kg daily, for 12 months. After the third month of treatment, doses of the CBD and concomitant AEDs could be adjusted monthly in almost all patients in order to optimize seizure control. 15 patients achieved the initial maximum dose of 25 mg/kg/day of CBD, while five achieved the highest dose of 50 mg/kg/day of the CBD, and at this dose, none reported CBD-related AEs. Instead, six patients decreased the dose of CBD during the study in order to alleviate AEs and interactions with concurrent AEDs. 66.7% of patients reported AEs and among them, drowsiness, ataxia and diarrhoea. Three months after the treatment, in four patients a reduction in seizure rate greater than 80% was recorded and one patient became seizure-free and he remained free until the twelfth month. The results also show that in patients took CBD and CLB the response rate after 3 months of treatment was 58.3% against 33.3% in patients who did not take CLB. Given the results reported by the authors in this study, the CBD can be considered valid and safe in the treatment of refractory epilepsy in the TSC.

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Table 2

The phase 3 clinical trial <"type":"clinical-trial","attrs":<"text":"NCT02224690","term_id":"NCT02224690">> NCT02224690 (GWPCARE4) included 171 patients (aged between 2 and 55 years) with a diagnosis of LGS. Participants had to have taken one or more antiepileptic drugs (the most used was lamotrigine, valproate and CLB) at a stable dose for at least 4 weeks prior to screening as well as interventions for epilepsy. The first endpoint was to aim the efficacy of the CBD oral solution (GWP42003-P) as adjunctive treatment in reducing the number of drop seizures when compared to the placebo. The secondary endpoint was to assess the safety of CBD by measuring AEs using standard severity measures. Individuals were divided into two groups: 85 received placebo and 86 received a CBD at a dose of 20 mg/kg/day for 14 weeks. SAEs (pneumonia, viral infection, alanine aminotransferase increased, aspartate aminotransferase increased, γ-glutamyltransferase increased) occurred in the 23.26% of CBD group and in 4.71% of patients in the placebo group. Serious TEAEs (increased levels of alanine aminotransferase, aspartate aminotransferase and γ-glutamyltransferase) occurred in four patients in the CBD group. Instead, the most common no serious-AEs (vomiting, diarrhoea, loss of appetite and drowsiness) occurred in the 61.63% of CBD group and in 50.59% of patients in the placebo group. After 14 weeks of treatment, the monthly frequency of seizures decreased by a median of 43·9% from baseline in the CBD group. A reduction in seizures frequency of 50% or more, was reported in 44% of patients in the CBD group and in 24% of patients in the placebo group. The study found that in many patients treated with antiepileptic drugs that included CLB, a higher onset of somnolence was observed. High levels of transaminases were recorded in patients treated with valproate. Nevertheless, the high rate of AEs, the results showed that the administration of long-term CBD oral solution in patients with LGS determines the reduction in seizure frequency compared to placebo [76].

See also  crd cbd

Cannabidiol (CBD) is one of the cannabinoids with non-psychotropic action, extracted from Cannabis sativa. CBD is a terpenophenol and it has received a great scientific interest thanks to its medical applications. This compound showed efficacy as anti-seizure, antipsychotic, neuroprotective, antidepressant and anxiolytic. The neuroprotective activity appears linked to its excellent anti-inflammatory and antioxidant properties. The purpose of this paper is to evaluate the use of CBD, in addition to common anti-epileptic drugs, in the severe treatment-resistant epilepsy through an overview of recent literature and clinical trials aimed to study the effects of the CBD treatment in different forms of epilepsy. The results of scientific studies obtained so far the use of CBD in clinical applications could represent hope for patients who are resistant to all conventional anti-epileptic drugs.

Table 1

The clinical trial <"type":"clinical-trial","attrs":<"text":"NCT02461706","term_id":"NCT02461706">> NCT02461706 will assess the safety and efficacy of CBD when administered as adjunctive therapy in 50 children (2 to 16 years) who have resistant to AEDs. Patients treated with AEDs were to have stabilized doses at least 4 weeks prior to enrolling. The study established the starting dose of 25 mg/kg/day. Maximum dose titration should be achieved in most patients within 5 weeks. The patients will be clinically evaluated at baseline, once a month for three months and once every three months thereafter. In addition, to ensure the safety of the study, all patients who reached the maximum dose (more than 600 mg of daily) of the CBD will be monitored at least once a month until the steady state of the maintenance dose was reached.

The study conducted by Geffrey, et al. [72], approved by Massachusetts General Hospital (MGH) Institutional Review Board (IRB) evaluated the CBD interaction with CLB. The aim of this study was to evaluate possible interactions between CBD and CLB, assessing its efficacy, safety and pharmacokinetics. For this study, 13 patients (4 to 19 years) with refractory epilepsy and treated with CLB were recruited. Patients started taking CBD at a dose of 5 mg/kg/day and treated up by 5 mg/kg/day each week to a dose of 25 mg/kg/day, for 8 weeks. CLB was administered daily at a stable dose of 0.5 mg/kg that was decreased during the study when side effects were observed. The plasma levels of CBD, CLB and [N-CLB] were measured at baseline and at weeks 4 and 8 of treatment. The results of the efficacy study showed a 50% convulsion reduction in nine out of 13 subjects, corresponding to a 70% response rate. In two patients, however, there was an increase in the frequency of seizures during the treatment period, therefore the dose of CLB was reduced. Increases in plasma levels of CBD, CLB and its metabolite were recorded. Already in the fourth week, the mean of CBL levels had been an increase of 60 ± 80%, while the mean in [N-CLB] was an increase of 500 ± 300%. The results of the safety study show that in 77% subjects AEs were reported as somnolence (n = 6), ataxia (n = 2), irritability (n = 2), restless sleep (n = 1), urinary retention (n = 1), tremor (n = 1) and loss of appetite (n = 1). After adjusting the doses of CLB all AEs were resolved. Therefore, the results reported by the authors show an interaction between CBD and CLB, and that CBD influences [N-CLB] levels much more than CLB levels.